Studies will be undertaken to gain further insight into the mechanism of action of the interferons and to ascertain how they can best be employed therapeutically. We are proposing to biochemically characterize those proteins whose synthesis is induced following interferon treatment. This characterization will include the partial amino acid sequencing of these proteins. In addition to the induction of new proteins following interferon treatment, other protein changes have been observed in cells whose growth is inhibited by interferon treatment. These changes will be studied and a determination will be made as to whether they can be used to predict which cells will be growth inhibited by interferon treatment. If so, methodologies will be developed which will allow for a determination of the responsiveness of freshly removed tumor tissues to the effects of the different human interferons. To learn more about the effects of the interferons, a variety of cell lines will be treated with the different interferons and their antiviral response, against several different viruses, and their anticellular response will be determined. An attempt will then be made to correlate these effects with the interferon induced enzymes and proteins produced by these cells. The human interferons and tumor necrosis factors have been observed to exhibit a synergistic antiproliferative effect and the antiviral effects of the interferons have been observed to be enhanced by the tumor necrosis factors. Experiments will be undertaken to study these interactions to determine the mechanism by which they occur. This study is designed to provide information which will allow for the optimal combined use of these biological response modifiers in the clinic.